Significant risk of COVID-19 and related-hospitalization among patients with adrenal insufficiency: A large multinational survey.

Objective: To determine self-reported incidence and potential risk factors for COVID-19 in patients with adrenal insufficiency (AI). Methods: A 27-item AI survey was developed for AI and COVID-19 status, vetted by specialists and patients, and distributed via social media, websites, and advocacy groups. Participation was voluntary and anonymous. Data were collected from September 20th, 2020 until December 31st, 2020. Results: Respondents (n=1291) with self-reported glucocorticoid treatment for AI, completed the survey, with 456 who reported having symptoms and were screened for COVID-19 during 2020; 40 tested positive (+ve), representing an 8.8% incidence. Of the COVID-19+ve, 31 were female (78%), with mean age of 39.9 years. COVID-19 among AI patients occurred most commonly in those aged 40-59 years (n=17; 42.5%); mean time since AI diagnosis was 13.5 years (range 0.2-42.0 years). Pulmonary disease, congenital adrenal hyperplasia, and higher maintenance doses of glucocorticoids were significantly associated with +ve COVID-19 (p=0.04, p=0.01, and p=0.001, respectively. In respondents the cumulative incidence of COVID-19+ve during 2020 was 3.1%; greater than the 1.03% worldwide-incidence reported by WHO, by December 31st, 2020. There was a 3-fold (95% CI 2.16-3.98) greater relative risk (RR) of COVID-19 infection and a 23.8- fold (95% CI 20.7-31.2) RR of hospitalization in patients with AI, compared with the global population. Conclusion: A markedly raised RR of COVID-19 and hospitalization in respondents reporting chronic AI was detected. We found that a diagnosis of congenital adrenal hyperplasia, age>40 years, male gender, pulmonary disease, and higher maintenance doses of glucocorticoids were associated with greatest risk.

Tumor-induced osteomalacia: a case report.

BACKGROUND: Tumor-induced osteomalacia is a rare, acquired paraneoplastic syndrome, including hypophosphatemia, high serum alkaline phosphatase, reduced active vitamin D, suboptimal bone mineral density, bone pain, fragility fractures, and muscle weakness. CASE PRESENTATION: We report a case of 74-year-old male of mixed ancestry with hypophosphatemia resistant to treatment despite optimal compliance, associated with profound reduction of bone mineral density and multiple nontraumatic fractures, including bilateral rib fractures, lower-thoracic (T11, T12) vertebrae, and two fractures involving the surgical and anatomical neck of the right humerus. We discuss an approach to identifying the underlying cause of hypophosphatemia associated with fragility fractures, and options for management of this rare condition. CONCLUSION: Although rare, tumor-induced osteomalacia can be diagnosed if a logical stepwise approach is implemented. Surgery could be curative if the tumor is properly located and is resectable.

Challenge of coexisting type 2 diabetes mellitus and insulinoma: a case report.

BACKGROUND: Insulinomas are rare clinical entities, but concurrent diabetes mellitus is even more uncommon, and the combination is easily missed. Recurrent hypoglycemia could be misconstrued as improved glycemic control. We present an unusual patient with type 2 diabetes and neuroglycopenia, with apparent improved glycemic control due to an insulinoma. CASE PRESENTATION: A 54-year-old mixed ancestry man with a positive family history of type 2 diabetes mellitus was diagnosed with type 2 diabetes mellitus and hypertension 8 years prior to admission. He presented with episodes of abnormal behavior and hypoglycemia. Inappropriately high insulin and C-peptide concentrations were identified at the time of hypoglycemia. Despite poor adherence to his diabetic treatment, he had no target organ damage relating to diabetes, and his hemoglobin A1c (HbA1c) was 5.3%. A diagnosis of insulinoma was made, and he was started on diazoxide, with endoscopic ultrasound revealing a possible lesion in the pancreatic tail measuring 12 mm × 12 mm. A fine-needle aspiration biopsy could not be performed due to overlying splenic arteries and the risk of vascular perforation. An intraoperative ultrasound confirmed a 15 mm × 10 mm tumor in the pancreatic tail, necessitating a partial pancreatectomy and splenectomy, which were curative. A well-differentiated intermediate grade 2 pancreatic neuroendocrine tumor producing insulin was confirmed on histopathology. CONCLUSIONS: Recurrent, progressive hypoglycemia and improved glycemic control in a diabetic, without an alternative explanation, may suggest an insulinoma. Insulinomas that exist with type 1 diabetes mellitus, particularly malignant insulinomas, must have escaped autoimmune attack through lack of autoantigen expression. Computed tomography on its own may be insufficiently sensitive for diagnosis of insulinomas, whereas endoscopic and intraoperative ultrasonography may improve the identification of the culprit lesion.

Sleep, Cognition and Cortisol in Addison's Disease: A Mechanistic Relationship.

Sleep is a critical biological process, essential for cognitive well-being. Neuroscientific literature suggests there are mechanistic relations between sleep disruption and memory deficits, and that varying concentrations of cortisol may play an important role in mediating those relations. Patients with Addison's disease (AD) experience consistent and predictable periods of sub- and supra-physiological cortisol concentrations due to lifelong glucocorticoid replacement therapy, and they frequently report disrupted sleep and impaired memory. These disruptions and impairments may be related to the failure of replacement regimens to restore a normal circadian rhythm of cortisol secretion. Available data provides support for existing theoretical frameworks which postulate that in AD and other neuroendocrine, neurological, or psychiatric disorders, disrupted sleep is an important biological mechanism that underlies, at least partially, the memory impairments that patients frequently report experiencing. Given the literature linking sleep disruption and cognitive impairment in AD, future initiatives should aim to improve patients' cognitive performance (and, indeed, their overall quality of life) by prioritizing and optimizing sleep. This review summarizes the literature on sleep and cognition in AD, and the role that cortisol concentrations play in the relationship between the two.

Reduced Slow-Wave Sleep and Altered Diurnal Cortisol Rhythms in Patients with Addison's Disease.

OBJECTIVES: Cortisol plays a key role in initiating and maintaining different sleep stages. Patients with Addison's disease (AD) frequently report disrupted sleep, and their hydrocortisone medication regimes do not restore the natural diurnal rhythm of cortisol. However, few studies have investigated relations between sleep quality, especially as measured by polysomnographic equipment, and night-time cortisol concentrations in patients with AD. METHODS: We used sleep-adapted EEG to monitor a full night of sleep in 7 patients with AD and 7 healthy controls. We sampled salivary cortisol before bedtime, at midnight, upon awakening, and at 30-minutes post-waking. RESULTS: Controls had lower cortisol concentrations than patients before bedtime and at midnight. During the second half of the night, patient cortisol concentrations declined steeply, while control concentrations increased steadily. Whereas most controls experienced a positive cortisol awakening response, all patients experienced a decrease in cortisol concentrations from waking to 30-minutes post-waking (P = .003). Patients experienced significantly lower proportions of slow-wave sleep (SWS; P = .001), which was associated with elevated night-time cortisol concentrations. CONCLUSION: Overall, these results suggest that patients with AD demonstrate different patterns of night-time cortisol concentrations to healthy controls, and that relatively elevated concentrations are associated with a reduction of SWS. These hormonal and sleep architectural aberrations may disrupt the routine sleep-dependent processes of memory consolidation, and hence may explain, at least partially, the memory impairments often experienced by patients with AD.

Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study.

Context: Patients with Addison's disease (AD) have increased cardiovascular mortality. Objective: To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. Design: A cross-sectional, single-center, case-control study. Subjects: Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. Main outcome measures: The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. Results: The mean ± standard deviation age of all subjects was 53 ± 14 years; mean BMI, 25 ± 4 kg/m2; and mean duration of AD, 17 ± 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P < 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC), >1] and vasodilatory protective marker was decreased (FC, <1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Conclusion: Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.

Impaired quality and efficiency of sleep impairs cognitive functioning in Addison's disease.

BACKGROUND: Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. Periods of sub- and supra- physiological cortisol levels experienced by patients with AD likely induce disrupted sleep. Given that healthy sleep plays an important role in memory consolidation, the novelty of the current study was to characterise, using objective measures, the relationship between sleep and memory in patients with AD, and to examine the hypothesis that poor sleep is a biological mechanism underlying memory impairment in those patients. METHODS: We used a within-subjects design. Ten patients with AD and 10 matched healthy controls completed standardised neuropsychological tests assessing declarative memory (Rey Auditory Verbal Learning Test) and procedural memory (Finger Tapping Task) before and after a period of actigraphy-measured sleep, and before and after a period of waking. RESULTS: Relative to healthy controls, patients with AD experienced disrupted sleep characterised by poorer sleep efficiency and more time spent awake. Patients also showed impaired verbal learning and memory relative to healthy controls (p=0.007). Furthermore, whereas healthy controls' declarative memory performance benefited from a period of sleep compared to waking (p=0.032), patients with AD derived no such benefit from sleep (p=0.448). Regarding the procedural memory task, analyses detected no significant between-group differences (all p's<0.065), and neither group showed significant sleep-enhanced performance. CONCLUSIONS: We demonstrated, using actigraphy and standardized measures of memory performance, an association between sleep disturbances and cognitive deficits in patients with AD. These results suggest that, in patients with AD, the source of memory deficits is, at least to some extent, disrupted sleep patterns that interfere with optimal consolidation of previously-learned declarative information. Hence, treating the sleep disturbances that are frequently experienced by patients with AD may improve their cognitive functioning.

Cardiovascular risk factors in patients with Addison's disease: a comparative study of South African and Swedish patients.

BACKGROUND: Patients with Addison's disease (AD) in Scandinavia have an increased risk for premature death due to cardiovascular disease (CVD). Serum lipids are important risk factors for CVD and vascular mortality. Replacement doses of hydrocortisone have historically been higher in Sweden than South Africa. The primary aim was to study the lipid profiles in a large group of patients with AD with the hypothesis that the lipid profile in patients in Sweden would be worse than in South Africa. METHODS: In a cross-sectional study, 110 patients with AD (55 from South Africa, 55 from Sweden) matched for age, gender, ethnicity and BMI were studied. Anthropometric measures, blood pressure, lipids, highly sensitive C-reactive protein (hs-CRP) and adiponectin were studied. RESULTS: All patients were Caucasian and the majority were women N = 36 (65.5%). Mean (standard deviation; SD) ages of the Swedish and South African patients were 52.9 (13.0) and 52.6 (14.4) years and BMI 25.3 (3.2) and 25.8 (4.1) kg/m2, respectively. The mean total daily hydrocortisone dose was greater in the Swedish patients than the South African patients, [33.0 (8.1) versus 24.3 (8.0) mg; p<0.0001]. South African patients had higher median (interquartilerange; IQR) triglycerides (TG) [1.59 (1.1-2.46) versus 0.96 (0.74-1.6) mmol/l; p<0.001], total cholesterol (TC) [6.02(1.50) versus 5.13 (0.87) mmol/l; p<0.001], LDL-C [4.43 (1.44) versus 2.75 (0.80) mmol/l; p<0.001] and median hs-CRP [2.15 (0.93-5.45) versus 0.99 (0.57-2.10) mg/L; p<0.003] and lower HDL-C [0.80 (0.40) versus 1.86 (0.46) mmol/l; p<0.001] than the Swedish patients. Approximately 20% of the patients in both cohorts had hypertension and diabetes mellitus. CONCLUSIONS: South African patients with AD have worse lipid profiles and higher hs-CRP compared to their matched Swedish patients, despite lower doses of hydrocortisone. It is uncertain at this time whether these are due to genetic or environmental factors.

9ß Polymorphism of the glucocorticoid receptor gene appears to have limited impact in patients with Addison's disease.

BACKGROUND: Addison's disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9ß polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. MATERIALS AND METHODS: 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. RESULTS: Genotype data for the 9ß polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9ß polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. CONCLUSIONS: This study did not identify any associations between the 9ß polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD.

Addison's disease symptoms--a cross sectional study in urban South Africa.

BACKGROUND: Addison's disease is a potentially life-threatening disorder, and prompt diagnosis, and introduction of steroid replacement has resulted in near normal life-expectancy. There are limited data describing the clinical presentation of Addison's disease in South Africa. It is hypothesised that patients may present in advanced state of ill-health, compared to Western countries. PATIENTS: A national database of patients was compiled from primary care, referral centres and private practices. 148 patients were enrolled (97 white, 34 mixed ancestry, 5 Asian and 12 black). METHODS: Demographic and clinical data were elicited using questionnaires. Biochemical data were obtained from folder reviews and laboratory archived results. RESULTS: The majority of the cohort was women (62%). The median and inter-quartile age range (IQR) of patients at enrolment was 46.0 (32.0-61.0) years, with a wide range from 2.8-88.0 years. The median and IQR age at initial diagnosis was 34.0 (20.0-45.0) years (range 0.02-77.0) years, indicating that at the time of enrolment, the patients, on average, were diagnosed with Addison's disease 12 years previously. Hyperpigmentation was observed in 76%, nausea and vomiting occurred in more than 40%, and weight loss was noted in 25%. Loss of consciousness as a presenting feature was recorded in 20%. with a 95% confidence interval [CI] of (14-28%) and shock occurred in 5% CI (1.5-8.5%). Case-finding was recorded at 3.1 per million. CONCLUSIONS: The usual constellation of hyperpigmentation, nausea, vomiting and weight loss suggests Addison's disease, but a significant proportion present with an advanced state of ill-health and Addisonian crises. A lower prevalence rate, compared to Western countries is suggested.

Amiodarone-induced thyroid dysfunction.

BACKGROUND: Little is known about the frequency of thyroid dysfunction (TD) associated with amiodarone therapy in southern Africa. OBJECTIVES: To determine the incidence of TD in a cohort of patients initiated on amiodarone therapy at a cardiac clinic in Cape Town, South Africa, believed to be an iodine-replete area. PATIENTS: Pharmacy records were used to obtain the names of patients who received amiodarone between November 1999 and December 2002. RESULTS: The sample size was 194, but data analysis was limited to the 163 patients for whom there were complete data. The mean age +/- standard deviation (SD) was 59.0 +/- 15.0 years (range 22 - 89 years). There were 67 female and 96 male patients. The indications for amiodarone therapy were supraventricular tachycardias (N = 102, 62.6%), ventricular tachycardia (N = 55, 33.7%), and prophylaxis against tachycardias (N = 3, 1.8%). The indication was uncertain in 3 patients (1.8%). The median duration of amiodarone treatment was 679.0 days (quartile deviation (QD) 1172 days, range 3 - 6425 days) in the whole cohort. The median duration of amiodarone therapy until new TD was 943 days (QD 1185 days), significantly longer than in patients who remained euthyroid (547 days, QD 1135 days) (P = 0.05). There were 45 new TD cases (27.6%): 11 patients (6.7%) were thyrotoxic, 1 (0.6%) transient thyrotoxicosis, 1 (0.6%) subclinical hyperthyroidism, 13 (8.0%) had subclinical hypothyroidism, 12 (7.4%) hypothyroidism and 7 (4.3%) had minor changes in thyroid function. CONCLUSIONS: We found a high incidence of new-onset TD, similar to the highest rates reported internationally. Local factors responsible for this need to be investigated.